Diagnostic Microbiology and Infectious Disease 75 (2013) 331336

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Diagnostic Microbiology and Infectious Disease

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Review

Tigecycline: an update
Gary E. Stein a,, Timothy Babinchak b, 1
a
Michigan State University, East Lansing, MI 48824, USA
b
Phoenixville, PA 19460, USA

a r t i c l e i n f o a b s t r a c t

Article history: Tigecycline is a broad-spectrum antibiotic with activity against difcult-to-treat pathogens such as
Received 17 August 2012 methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus spp., Acinetobacter baumannii,
Received in revised form 10 December 2012 and Gram-negative bacterial strains that produce extended-spectrum -lactamases. Minimal organ toxicity
Accepted 18 December 2012
and lack of dosage adjustment in most patients are important considerations for tigecycline use. Tigecycline
Available online 26 January 2013
has been shown to be as effective and safe as standard antimicrobial therapy for treatment of adults with
Keyword:
complicated intra-abdominal infections, complicated skin and skin structure infections, and community-
Tigecycline acquired bacterial pneumonia. The clearest applications of tigecycline are for on-label indications. Whether
tigecycline should be utilized as therapy for other infections including hospital-acquired infections with a
high likelihood of multidrug-resistant pathogens is a complex issue that requires ongoing assessment. This
article offers an updated overview of tigecycline clinical studies, current microbial resistance patterns,
pharmacokinetic/pharmacodynamic investigations, and safety analyses.
2013 Elsevier Inc. All rights reserved.

1. Introduction patients with community-acquired bacterial pneumonia (Tanaseanu

Tigecycline is the prototype compound of a new class of
antimicrobial agents known as glycylcyclines (Olson et al., 2006).
This derivative of minocycline provides clinicians with a novel,
expanded broad-spectrum antibiotic with activity against difcult-
to-treat pathogens such as methicillin-resistant Staphylococcus aureus
(MRSA), vancomycin-resistant Enterococcus spp., Acinetobacter bau-
mannii, and Gram-negative bacterial strains that produce extended-
spectrum -lactamases (ESBL) (Noskin, 2005). Moreover, tigecycline
causes minimal organ toxicity, and dosage adjustment is unnecessary
in most patient populations (Stein and Craig, 2006). With these
qualities, tigecycline has the potential to be utilized in a variety of
clinical settings (Livermore, 2005).
Tigecycline was initially approved by the US Food and Drug
Administration (FDA) in 2005 and the European Medicines Agency in
2006 for the treatment of adults with complicated intra-abdominal
infections (cIAI) and complicated skin and skin structure infections
(cSSSI) (Babinchak et al., 2005; Ellis-Grosse et al., 2005). In 2008,
tigecycline also received FDA approval for the treatment of adult
This publication was sponsored by Pzer Inc. Gary Stein has received research grants
from Pzer Inc. Tim Babinchak is a former employee of Pzer Inc. Medical writing
support was provided by Charlotte Kenreigh of UBC Scientic Solutions and funded by
Pzer Inc.
Corresponding author. Tel.: +1-517-353-5126; fax: +1-517-353-1922.
E-mail address: Gary.Stein@hc.msu.edu (G.E. Stein).
1
Former employee of Pzer Inc.
et al., 2008). Since its introduction, several other clinical uses for
tigecycline have been investigated. Uses not currently approved by
the FDA include hospital-acquired pneumonia (HAP) and ventilator-
associated pneumonia (VAP), diabetic foot infections, rescue therapy
for infections due to multidrug-resistant (MDR) pathogens, nosoco-
mial urinary tract infections (UTIs), and refractory Clostridium difcile
infection (Cunha et al., 2007; Sabol et al., 2009; Freire et al., 2010;
Gandjini et al., 2012; Herpers et al., 2009; Kelesidis et al., 2008;
Schafer et al., 2007).
This article provides an updated review of tigecycline and includes
clinical trial results of FDA-approved and FDA-unapproved indica-
tions, microbiology, pharmacokinetics/pharmacodynamics (PK/PD),
and safety (Stein and Craig, 2006).
2. Clinical studies
2.1. FDA-approved indications
The initial approval of tigecycline (100 mg followed by 50 mg
every 12 h) for the treatment of cIAI and cSSSI was based on the
results of 2 randomized, double-blind studies comparing tigecycline
to vancomycin/aztreonam and imipenem, respectively (Babinchak et
al., 2005; Ellis-Grosse et al., 2005). More recently, FDA approval for the
treatment of community-acquired bacterial pneumonia was based on
2 phase 3, randomized, double-blind studies that compared tigecy-
cline with levooxacin (Tanaseanu et al., 2008). More than 800
patients were studied in the community-acquired pneumonia (CAP)

0732-8893/$ see front matter 2013 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.diagmicrobio.2012.12.004
332 G.E. Stein, T. Babinchak / Diagnostic Microbiology and Infectious Disease 75 (2013) 331336
trials; 47% had a Fine pneumonia severity index score of III to V. There
were no signicant differences between the 2 treatment groups in
hospital length of stay, mean duration of antibiotic therapy, and rate
of rehospitalization. Overall, clinical cure rates and microbiologic
responses were similar in the 2 treatment arms.
2.2. Hospital-acquired pneumonia
Because of its in vitro activity against MDR pathogens, tigecycline
also has been studied for the treatment of HAP, including VAP. The
ndings of a large randomized, double-blind comparative trial of the
combination of tigecycline/ceftazidime versus imipenem/vancomy-
cin for the treatment of HAP have been reported (Freire et al., 2010).
Tigecycline dosing reected the approved dose in the product label.
This multicenter study evaluated 945 patients with HAP, including
235 with VAP. Only one of the coprimary end points, noninferiority
for the clinical modied intention-to-treat population, was met. Cure
rates were 67.9% for tigecycline-treated patients and 78.2% for
imipenem-treated patients in the clinically evaluable population
(P = 0.120; 95% condence interval [CI], 17.8 to 3.0). Acute
Physiology and Chronic Health Evaluation (APACHE) II scores did not
account for the differences between treatment groups. However, a
statistical interaction occurred between the VAP and non-VAP
subgroups, with signicantly lower cure rates in patients with VAP
treated with tigecycline (47.9%) compared with patients with VAP
treated with imipenem (70.1%). As the study was powered for the
overall response (HAP/VAP), the lower cure rates in the VAP subset
led to a failure to achieve the predened statistical signicance of a
15% difference in treatment groups. A similar study exploring higher
doses of tigecycline (150 mg followed by 75 mg every 12 h or 200
mg followed by 100 mg every 12 h) versus imipenem in HAP and
VAP (clinicaltrials.gov NCT00707239) was recently discontinued
owing to insufcient enrollment (Gandjini et al., 2012). In a
retrospective review of patients with VAP caused by MDR A.
baumannii, tigecycline alone or in combination with another
antimicrobial produced clinical cures in 18 of 22 patients (82%)
(Schafer et al., 2007). One patient with VAP and bacteremia
developed resistance to tigecycline during therapy.
2.3. Diabetic foot infection
Tigecycline 150 mg once daily has been compared with ertapenem
plus vancomycin in a multicenter, randomized, double-blind study of
hospitalized patients with diabetic foot infections (Sabol et al., 2009).
For the clinically evaluable population, 77.5% of tigecycline-treated
patients and 82.5% of comparator-treated patients were cured. The
tigecycline regimen did not meet the primary study end point of
noninferiority to ertapenem vancomycin based on a prespecied
10% noninferiority margin. Treatment groups were relatively bal-
anced for baseline characteristics, including severity of illness scores
as assessed by the infection component of the PEDIS (Perfusion,
Extent/size, Depth/tissue loss, Infection, and Sensation) system.
However, cure rates varied by geographic region and discontinua-
tions owing to adverse events were not evenly balanced between
treatment groups. The high tigecycline dose was relatively well
tolerated, and adverse events were similar to those previously
reported (Secondo et al., 2010; Swoboda et al., 2008; Tanaseanu et
al., 2008).
2.4. Infection with multidrug-resistant pathogens
The effectiveness of tigecycline for the treatment of infection
with MDR pathogens has been studied by several investigators. In a
phase 3, noncomparative study of tigecycline in the treatment of
patients with selected infections due to MDR Gram-negative
bacteria, clinical cures were achieved in 72% (26/36) of patients
(Vasilev et al., 2008). The majority of patients had cSSSIs (67%), and
the mean APACHE II score in the microbiologically evaluable
population was 9. Microbiologic eradication occurred in 75% (3/4)
and 65% (11/17) of patients with infections due to Enterobacter-
iaceae and A. baumannii, respectively.
Anthony et al. (2008) reviewed 18 patients who received
tigecycline (7 days) for the treatment of serious infections caused
by MDR Gram-negative bacilli. FDA tigecycline breakpoints used for
Enterobacteriaceae were applied to Acinetobacter spp. Of the patients
with A. baumannii infection, 5/9 isolates demonstrated intermediate
resistance (N2 or b8 mg/L) and 4 of these patients (3 with VAP, 1 with
bacteremia) died, while 0 of 4 patients with isolates susceptible to
tigecycline died. In addition, the researchers observed persistent
bacteremia in patients with susceptible isolates of A. baumannii,
Escherichia coli, and Klebsiella pneumoniae. The data from this
investigation suggest that pretherapy tigecycline minimum inhibitory
concentrations (MICs) of A. baumannii may predict clinical outcome
and raise concern about the routine use of tigecycline for bacteremia.
In a review of 33 patients, tigecycline was used alone (26 patients)
or in combination with another antibiotic to treat infections (e.g., cIAI,
bacteremia, pneumonia, and UTI) due to MDR Enterobacteriaceae
(Kelesidis et al., 2008). A total of 23 (70%) patients achieved
resolution of their infection. Prolonged administration (N21 days) of
tigecycline was required in 5 patients, and a rise in tigecycline MIC
was observed in 1 patient with HAP and empyema. These in-
vestigators also reviewed tigecycline treatment of MDR Acinetobacter
infections (Karageorgopoulos et al., 2008). The review included data
from 42 severely ill patients. The majority of these patients had
pneumonia (31 patients; concomitant bacteremia was present in 4
patients) and 4 patients had bacteremia alone. Tigecycline therapy
was used in combination with other antimicrobials in 28 (67%)
patients, and clinical success was achieved in 32 (76%) patients. In 3
patients, resistance to tigecycline developed during treatment.
Tigecycline use in 29 patients with Acinetobacter infections was
reviewed in a case series (Gallagher and Rouse, 2008). In these
patients, tigecycline was started a median of 30 days into the hospital
stay and therapy was continued for a median of 11 days. Concurrent
antibiotics were utilized in 17 of 29 courses (59%) of therapy.
Pneumonia was the most common infection and 24 (83%) patients
were in the intensive care unit. Microbial eradication was evident in
11 of the 25 patients (44%) with evaluable microbiologic data. Of the
29 treatment courses, positive outcomes were observed in 8 (28%); 19
(68%) patients did not survive to discharge. Susceptibility testing
was performed on 11 isolates; none of these isolates were susceptible
to tigecycline.
In another retrospective review of infections caused by MDR A.
baumannii, tigecycline was the sole antibiotic for treatment in 15 of 34
patients (44%) (Gordon and Wareham, 2009). All isolates had an
initial tigecycline MIC of b2 mg/L. The indications for therapy included
bacteremia (n = 9), respiratory infections (n = 9), bone/joint/soft
tissue infection (n = 10), IAI (n = 5), and intra-cranial infection (n =
1). A positive clinical response occurred in 23 (68%) patients. A.
baumannii was eradicated from the site of infection in only 10 of these
patients. A positive microbiologic and clinical response was docu-
mented in only 56% of patients with bacteremia. Three patients had
new episodes of Gram-negative bacteremia while receiving treatment
with tigecycline.
2.5. Bacteremia
The use of tigecycline for the treatment of bacteremia is
controversial because of its low serum concentrations. In a pooled,
retrospective data analysis of phase 3 clinical trials, 91 patients being
treated with tigecycline for a cSSSI, cIAI, or CAP had secondary
bacteremia (Gardiner et al., 2010). cIAI was the most common
indication for treatment (48% of patients) followed by CAP and cSSSI.
 G.E. Stein, T. Babinchak / Diagnostic Microbiology and Infectious Disease 75 (2013) 331336 333

The median duration of treatment was approximately 9 days. Table 1

Treatment with tigecycline was successful in 81% of these patients, Antimicrobial susceptibility of methicillin-susceptible Staphylococcus aureus (MSSA)
and methicillin-resistant S. aureus (MRSA) collected between 2004 and 2012 against
and cure rates were similar for patients with S. aureus, Streptococcus the Tigecycline Evaluation and Surveillance Trial panel of antimicrobial agents
pneumoniae, and Enterobacteriaceae isolates. All but one of these (T.E.S.T., 2012).
isolates had a tigecycline MIC 1 mg/L. Of the 9 patients with
2012a 2011 20042012
persistent bacteremia (blood isolate N24 h after starting therapy), 6
continued to receive tigecycline and achieved a clinical cure. It is MIC90 %S MIC90 %S MIC90 %S
important to point out that the majority of these patients had MSSA n = 26 n = 1605 N = 18,389
community-acquired infections and relatively low APACHE II scores (3998/14391)b
(mean, 7.3). AMC 2 100 1 100 1 100
Ampicillin 32 23.08 16 25.73 32 20.62
2.6. Urinary tract infection Ceftriaxone 4 100 4 99.25 4 98.77
c c c c
Imipenem 0.25 100
Levooxacin 0.5 96.15 0.5 93.02 0.5 92.82
Debate over the effectiveness of tigecycline for the treatment of Linezolid 2 100 2 100 4 100
UTIs due to MDR bacteria is based on the concern that only 15% of Meropenem 0.25 100 0.25 99.75 0.25 99.96
tigecycline is excreted unchanged in the urine with standard dosing Minocycline 0.5 100 0.5 99.44 0.5 99.00
(Nix and Matthias, 2010). No large clinical trial using tigecycline has Penicillin 16 19.23 16 22.62 16 17.77
TZP 2 100 1 100 2 99.99
been conducted in patients with UTIs, but several investigators have Tigecycline 0.25 100 0.25 100 0.25 100
reported successful outcomes with tigecycline therapy in patients Vancomycin 1 100 1 100 1 100
with a UTI (Cunha et al., 2007; Geerlings et al., 2010; Krueger et al.,
2008). These were cases of complicated UTIs due to MDR Gram- MRSA n = 12 n = 595 N = 11,746
negative pathogens and included 2 patients with end-stage renal Levooxacin 8 66.67 64 17.48 64 20.78
disease. Tigecycline was utilized as primary and secondary therapy in Linezolid 2 100 2 100 2 100
Minocycline 8 83.33 1 97.98 4 93.81
these patients.
Tigecycline 0.5 100 0.25 100 0.25 99.82
Vancomycin 1 100 1 100 1 100
2.7. C. difcile infection
% S = Percent susceptible; AMC = amoxicillinclavulanate; MIC90 = minimum
inhibitory concentration at which 90% of isolates inhibited; TZP = piperacillin
Tigecycline is highly active against C. difcile, and treatment with tazobactam.
tigecycline does not appear to increase the risk of C. difcile infection a
Data for 2012 are not complete.
b
(Wilcox, 2007). Furthermore, tigecycline has been used as adjunctive Number of isolates tested against imipenem/meropenem.
c
Data not given for imipenem in 2011 and 2012 as antimicrobial not tested.
therapy for refractory C. difcile infection (Herpers et al., 2009). In 4
cases of severe refractory C. difcile infection, intravenous tigecycline
(alone or in combination with vancomycin) was successful in approved indication and interpretive criteria for in vitro susceptibility
alleviating symptoms within 1 week of treatment and no relapses testing, the FDA tigecycline breakpoints used for Enterobacteriaceae
were observed. This report suggests that intravenous tigecycline is a have been applied to Acinetobacter spp. A review by Jones et al. (2007)
feasible alternative antimicrobial in the treatment of C. difcile revealed an unacceptable error rate (23.3%), i.e., false resistance, by
infection and that further investigations are warranted. disk diffusion testing using these criteria. Using Clinical and
Laboratory Standards Institute methodology, the authors reported
3. Microbiology that an adjustment of tigecycline disk diffusion breakpoints (suscep-
tible/resistant) to 16 or 12 mm reduced inter-method errors to an
Tigecycline has maintained in vitro activity against a wide acceptable level of 9.7% (Jones et al., 2007).
spectrum of aerobic and anaerobic bacteria. Global in vitro activity Agar diffusion testing methods for Acinetobacter spp. have been
of tigecycline against Gram-positive organisms collected between further complicated by reports of varying results depending on the
2004 and 2009 from the Tigecycline Evaluation and Surveillance Trial Mueller-Hinton agar used in the testing. The interference of calcium
(T.E.S.T., 2012) demonstrated that antimicrobial activity against and magnesium with tetracycline activity that has been known for
tested organisms, including resistant organisms (i.e., MRSA), was decades is not a factor in tigecycline susceptibility testing (D'Amato et
maintained over the 6-year period (Dowzicky and Chmelarova, 2011). al., 1975). However, high concentrations of manganese in Mueller-
This activity continues to be maintained; Table 1 provides an update Hinton agar have been associated with increased MICs determined by
to this report and includes cumulative data from 2011. both Etest and disk diffusion (Canigia and Bantar, 2008; Fernndez-
Similarly, in vitro activity of tigecycline against Gram-negative Mazarrasa et al., 2009; Thamlikitkul and Tiengrim, 2008). The MICs of
organisms has been preserved (Sader et al., 2011). Tigecycline activity tigecycline in media with low manganese content are considered
against E. coli (MIC 50/90, 0.12/0.25 mg/L) remains independent of more clinically relevant, as the concentration of manganese in human
ESBL phenotype or resistance to other antimicrobials. For Klebsiella serum is considerably lower than that found in articial media. It is
spp., 97.9% of ESBL-producing Klebsiella spp. and 98.2% of imipenem important to conrm any discrepant results of tigecycline in vitro
nonsusceptible strains remain susceptible to tigecycline (MIC 50/90, testing using the recognized standard of broth microdilution
0.5/1.0 mg/L for both subsets). No trend toward decreased tigecycline (Bradford et al., 2005).
activity over time was observed for either Enterobacter spp. or The continuing development of multidrug resistance worldwide
Acinetobacter spp. in this study. A more recent study of European poses a challenge to clinicians regarding the use of new or potent
blood culture isolates encompassing the years 2004 to 2009 also antibiotics. The development of resistance to any particular agent or
revealed no decline in tigecycline susceptibility against Gram- class has often been shown to correlate with its overall use in a
negative organisms (Andrasevic and Dowzicky, 2012). population. For tigecycline, intrinsic resistance is known to occur in
The increasing occurrence of Acinetobacter spp. as pathogens Pseudomonas aeruginosa via the MexXY multidrug efux system
causing serious infections has prompted the search for therapeutic (Dean et al., 2003) and similarly in the Proteeae by the AcrAB system
alternatives to the carbapenems and polymyxin class agents. (Visalli et al., 2003). These pumps belong to the resistance/
Tigecycline has demonstrated in vitro activity against these organisms nodulation/division (RND) family and are often associated with
globally with MIC 50/90, 0.5/2.0 mg/L. However, without an FDA- multidrug resistance.
334 G.E. Stein, T. Babinchak / Diagnostic Microbiology and Infectious Disease 75 (2013) 331336
The development of tigecycline resistance in clinical isolates has
been exclusively associated with these multidrug efux mechanisms.
For Klebsiella and Enterobacter spp., resistance has been associated
with changes in the ramA component of the AcrAB system (Keeney et
al., 2007; Ruzin et al., 2005). In Acinetobacter spp., tigecycline
resistance is also associated with the RND-type efux system, AdeABC
(Ruzin et al., 2007). Because these systems may be selected for by
other antibiotics, reserving the use of tigecycline may not preserve its
future activity. For Gram-positive organisms, including MRSA, no
naturally occurring isolates with decreased susceptibility to tigecy-
cline have been identied to date.
4. Pharmacokinetics/Pharmacodynamics
Since the introduction of tigecycline, a number of PK/PD studies
have been completed. Because tigecycline exhibits time-dependent
killing and has a prolonged post-antibiotic effect, the ratio of the 24-h
area under the curve to the MIC (AUC/MIC) is the PK/PD index that
best correlates with the in vivo activity of tigecycline (Agwuh and
MacGowan, 2006). In an effort to further dene the PK prole of
tigecycline, population PK models were developed utilizing the
information obtained from the phase 2 and phase 3 clinical
development trials (Rubino et al., 2010; Van Wart et al., 2006).
When exposureresponse analyses utilizing these models were
performed for the efcacy of tigecycline in the treatment of cSSSI,
where S. aureus and streptococci are the predominant pathogens,
classication and regression tree analyses identied a signicant
AUC/MIC breakpoint of 17.9 (Meagher et al., 2007). A similar
analysis performed in cIAIs, for which E. coli and Bacteroides fragilis
are the predominant pathogens, identied a signicant AUC/MIC
breakpoint of 6.96 for both microbiologic and clinical response
(Passarell et al., 2008).
Additional PK/PD data from the CAP studies included simulta-
neous tissue and serum data analysis using population PK methods
to evaluate tigecycline penetration into epithelial lining uid (ELF)
and alveolar cells (AC) in healthy volunteers (Rubino et al., 2007).
The median (5th and 95th percentiles) penetration ratios for ELF
were 1.15 (0.561 and 5.23, respectively). However, extreme
variability in the ELF/tissue penetration modeling made it difcult
to predict this value in a given patient. With the use of the same
methodology to identify the appropriate population PK models from
the phase 3 clinical trials, exposureresponse analyses for tigecycline
in CAP identied an AUC/MIC breakpoint of 12.8 for efcacy
(Rubino et al., 2012).
Tigecycline concentrations in 3 critically ill, mechanically venti-
lated patients with pneumonia were reported by Burkhardt et al.
(2009). Steady-state ELF/plasma ratios ranged from 0.03 to 0.18 and
AC/plasma ratios from 3.95 to 34.3 when tigecycline was dosed at
50 mg twice daily following a 100-mg loading dose on day 1. The
clinical outcomes in these patients were not provided, although the
authors suggested that tigecycline may be underdosed in this clinical
situation (Burkhardt et al., 2009).
An analysis of PK data and clinical outcomes utilizing a phase 3
clinical trial of tigecycline-treated patients with HAP identied PK/PD
relationships between fAUC/MIC ratio or MIC and clinical and
microbiologic responses in the context of response modiers
(Bhavnani et al., 2012). Albumin was the most signicant predictor
for clinical or microbiologic response in the models generated. For the
clinical response model, fAUC/MIC ratios of 0.9 had 8.42 higher odds
of clinical success than fAUC/MIC ratios of b0.9 (P = 0.008). VAP status
and baseline pathogen MIC were additional factors associated with
microbiologic response (Bhavnani et al., 2012). Investigations such as
these, which utilize relationships between PK parameters and PD
responses in patient populations, can be very informative in dose
selection and clinical trial design.
5. Safety
In clinical trials, the predominant adverse events reported with
tigecycline use have been nausea and vomiting (Wyeth Pharmaceu-
ticals Inc., 2012). Cumulative incidence over 13 trials in various
indications has provided rates of 26% for nausea and 18% for vomiting.
While the mechanism for these adverse gastrointestinal events
remains unknown, they appear to be manageable with the use of
standard antiemetic therapies. For those individuals in whom nausea
occurs, the discontinuation rates in the blinded clinical trials are b5%
(Wyeth Pharmaceuticals Inc., 2012).
Since its introduction, several tetracycline class events also have
been reported with tigecycline. Pancreatitis, a known tetracycline-
related class adverse event, has been reported in association with
tigecycline treatment; consideration should be given to the cessation
of tigecycline treatment in patients who develop signs and symptoms
consistent with pancreatitis. Rash, including StevensJohnsontype
reactions, also has been reported. Other end-organ toxicities (e.g.,
renal, hepatic, or hematologic) have rarely been reported (Wyeth
Pharmaceuticals Inc., 2012).
Several recent meta-analyses of tigecycline study level data have
reported an increased mortality from clinical trials involving
tigecycline (Cai et al., 2011; Prasad et al., 2012; Tasina et al., 2011;
Yahav et al., 2011). The authors applied various methods of meta-
analysis including both random (Tasina et al., 2011) and xed-effect
(Yahav et al., 2011) methods to analyze different subgroups from
published studies. Their most important nding surrounds an
increased risk of mortality associated with the tigecycline treatment
group. Yahav et al. (2011) suggested decreased clinical and microbi-
ologic efcacy as a possible explanation; however, Tasina et al. (2011)
and Cai et al. (2011) were not able to identify any signicant
differences in efcacy or microbiologic eradication to account for the
results. One must be cautious in interpreting these results as study-
level data are often incomplete; moreover, clinical trials are not
designed to measure mortality and subgroup analysis can be
misleading (Assmann et al., 2000; Kim et al., 2010; Nguyen et al.,
2009; Parker and Naylor, 2000; Yusuf et al., 1991). Reviews of patient
level data may be more informative. An analysis of the complete
patient-level safety database acknowledged the difference in all-cause
mortality between the tigecycline and the comparator groups, and
presented the risk information by clinical infection type (McGovern et
al., 2011). Investigation of all variables available from the clinical
trials, however, was unable to determine a specic cause for the
increased mortality. Likewise, the FDA conducted its own evaluation
of the patient-level tigecycline database reaching similar conclusions
(Iarikov et al., 2011).
At the time of approval, a 1% mortality difference between
tigecycline and its comparators was noted. As more clinical trials
were completed, this 1% difference persisted and prompted a formal
benet/risk analysis at both the study and patient levels. The results of
this analysis have been incorporated in the product labeling and are
provided in Table 2 (Wyeth Pharmaceuticals Inc., 2012). Within the
approved indications, the risk difference for mortality with tigecycline
ranges from 0.2% in CAP to 0.8% in cIAI. The largest risk difference was
noted in VAP at 6.8% (95% CI, 2.1 to 15.7). While these analyses were
unable to identify a risk factor associated with mortality, the increased
risk of death in patients with VAP who were bacteremic at baseline
(9/18 tigecycline versus 1/13 comparator) should be taken into
consideration when tigecycline is used for this indication (Wyeth
Pharmaceuticals Inc., 2012).
6. Summary
Tigecycline has been shown to be as effective and safe as standard
antimicrobial therapy for the treatment of patients with cIAI, cSSSI,
and CAP. It is important to note that the phase 3 clinical trials of
 G.E. Stein, T. Babinchak / Diagnostic Microbiology and Infectious Disease 75 (2013) 331336 335

Table 2 References
Mortality by infection type (reproduced from Wyeth Pharmaceuticals Inc., 2012).
Andrasevic AT, Dowzicky MJ. In vitro activity of tigecycline and comparators against
Infection type Tigecycline Comparator Risk difference, % Gram-negative pathogens isolated from blood in Europe (20042009). Int J
(95% CI)a Antimicrob Agents 2012;39:11523.
n/N % n/N %
Anthony KB, Fishman NO, Linkin DR, Gasink LB, Edelstein PH, Lautenbach E. Clinical
cSSSI 12/834 1.4 6/813 0.7 0.7 (0.3 to 1.7) and microbiological outcomes of serious infections with multidrug-resistant
cIAI 42/1382 3.0 31/1393 2.2 0.8 (0.4 to 2.0) Gram-negative organisms treated with tigecycline. Clin Infect Dis 2008;46:
CAP 12/424 2.8 11/422 2.6 0.2 (2.0 to 2.4) 56770.
HAP 66/467 14.1 57/467 12.2 1.9 (2.0 to 6.3) Assmann S, Pocock SJ, Enos LE, Kasten LE. Subgroup analyses and other (mis)uses of
Non-VAPb 41/336 12.2 42/345 12.2 0.0 (4.9 to 4.9) baseline data in clinical trials. Lancet 2000;355:10649.
Agwuh KN, MacGowan A. Pharmacokinetics and pharmacodynamics of the tetracy-
VAPb 25/131 19.1 15/122 12.3 6.8 (2.1 to 15.7)
clines including glycylcyclines. J Antimicrob Chemother 2006;58:25665.
RP 11/128 8.6 2/43 4.7 3.9 (4.0 to 11.9)
Babinchak T, Ellis-Grosse E, Dartois N, Rose GM, Loh E, Tigecycline 301 and 306 Study
DFI 7/553 1.3 3/508 0.6 0.7 (0.5 to 1.8) Groups. The efcacy and safety of tigecycline for the treatment of complicated
Overall adjusted 150/3788 4.0 110/3646 3.0 0.6 (0.1 to 1.2)c intra-abdominal infections: analysis of pooled clinical trial data. Clin Infect Dis
CAP = Community-acquired pneumonia; cIAI = complicated intra-abdominal 2005;41:S35467.
infections; CI = condence interval; cSSSI = complicated skin and skin structure Bhavnani SM, Rubino CM, Hammel JP, Forrest A, Dartois N, Cooper CA, et al.
Pharmacological and patient-specic response determinants in patients with
infections; DFI = diabetic foot infections; HAP = hospital-acquired pneumonia; RP =
hospital-acquired pneumonia treated with tigecycline. Antimicrob Agents Che-
resistant pathogens; VAP = ventilator-associated pneumonia.
mother 2012;56:106572.
The studies include 300, 305, 900 (cSSSI), 301, 306, 315, 316, 400 (cIAI), 308 and 313 Bradford PA, Petersen PJ, Young M, Jones CH, Tischler M, O'Connell J. Tigecycline MIC
(CAP), 311 (HAP), 307 (resistant Gram-positive pathogen study in patients with testing by broth dilution requires use of fresh medium or addition of the
methicillin-resistant Staphylococcus aureus or vancomycin-resistant Enterococcus spp.), biocatalytic oxygen-reducing reagent oxyrase to standardize the test method.
and 319 (DFI with and without osteomyelitis). Antimicrob Agents Chemother 2005;49:39039.
a
Difference between the percentage of patients who died in tigecycline and Burkhardt O, Rauch K, Kaever V, Hadem J, Kielstein JT, Welte T. Tigecycline possibly
comparator treatment groups. The 95% CI for each infection type was calculated using underdosed for the treatment of pneumonia: a pharmacokinetic viewpoint. Int J
the normal approximation method without continuity correction. Antimicrob Agents 2009;34:1012.
b Cai Y, Wang R, Liang B, Bai N, Liu Y. Systematic review and meta-analysis of the
Subgroups of the HAP population.
c
Overall adjusted (random effects model by trial weight) risk difference estimate effectiveness and safety of tigecycline for treatment of infectious disease.
and 95% CI. Antimicrob Agents Chemother 2011;55:116272.
Canigia LF, Bantar C. Susceptibility testing of tigecycline against Acinetobacter spp. by
disc diffusion method: withdrawing a therapeutic option by varying the Mueller
Hinton agar? J Antimicrob Chemother 2008;62:14634.
tigecycline that led to FDA approvals for these indications mainly Cunha BA, McDermott B, Nausheen S. Single daily high-dose tigecycline therapy of a
included patients who were not seriously ill and had community- multidrug-resistant (MDR) Klebsiella pneumoniae and Enterobacter aerogenes
nosocomial urinary tract infection. J Chemother 2007;19:7534.
acquired infections. Moreover, few MDR pathogens were isolated
D'Amato RF, Thornsberry C, Baker CN, Kirven LA. Effect of calcium and magnesium ions
from these infections. The clearest applications of tigecycline are for on the susceptibility of Pseudomonas species to tetracycline, gentamicin polymyxin
these on-label indications, especially in patients with renal insuf- B, and carbenicillin. Antimicrob Agents Chemother 1975;7:596600.
ciency, a history of C. difcile infection, hypersensitivity to -lactams, Dean CR, Visalli MA, Projan SJ, Sum PE, Bradford PA. Efux-mediated resistance to
tigecycline (GAR-936) in Pseudomonas aeruginosa PAO1. Antimicrob Agents
or in those receiving multiple medications (Stein and Craig, 2006). Chemother 2003;47:9728.
Tigecycline has good in vitro activity against a wide range of Dowzicky MJ, Chmelarova E. Global in vitro activity of tigecycline and linezolid against
bacteria including several MDR pathogens. This broad spectrum of Gram-positive organisms collected between 2004 and 2009. Int J Antimicrob
Agents 2011;37:5626.
activity has led to multiple clinical investigations of tigecycline for the Ellis-Grosse EJ, Babinchak T, Dartois N, Rose G, Loh E, Tigecycline 300 and 305 cSSSI
treatment of both community-acquired and hospital-acquired in- Study Groups. The efcacy and safety of tigecycline in the treatment of skin and
fections, including use in seriously ill patients. This breadth of studies skin-structure infections: results of 2 double-blind phase 3 comparison studies
with vancomycin-aztreonam. Clin Infect Dis 2005;41:S34153.
has created confusion in determining the clinical positioning of Fernndez-Mazarrasa C, Mazarrasa O, Calvo J, del Arco A, Martnez-Martnez L. High
tigecycline (Livermore, 2005; Nathwani, 2005). concentrations of manganese in Mueller-Hinton agar increase MICs of tigecycline
Whether tigecycline should be utilized as therapy for hospital- determined by Etest. J Clin Microbiol 2009;47:8279.
Freire AT, Melnyk V, Kim MJ, Datsenko O, Dzyublik O, Glumcher F, et al, 311 Study
acquired infections with a high likelihood of MDR pathogens is a
Group. Comparison of tigecycline with imipenem/cilastatin for the treatment of
complex issue. For example, Acinetobacter spp. have developed hospital-acquired pneumonia. Diagn Microbiol Infect Dis 2010;68:14051.
resistance to many antimicrobials but are mostly susceptible (MICs Gallagher JC, Rouse HM. Tigecycline for the treatment of Acinetobacter infections: a case
series. Ann Pharmacother 2008;42:118894.
2 mg/L) to tigecycline. Tigecycline also exhibits good penetration
Gandjini H, McGovern PC, Yan JL, Dartois N. Clinical efcacy of two high tigecycline
into various tissues, such as the lungs. These attributes make dosage regimens versus imipenem/cilastatin in hospital-acquired pneumonia:
tigecycline an attractive choice for the treatment of HAP due to results of a randomised phase II clinical trial. Presented at: 22nd Annual Congress of
Acinetobacter spp., but there are several concerns with using this the European Congress of Clinical Microbiology and Infectious Diseases; March 31
April 3, 2012; London, United Kingdom; 2012.
agent in this clinical setting: i) patients with HAP are usually seriously Gardiner D, Dukart G, Cooper A, Babinchak T. Safety and efcacy of intravenous
ill and often have VAP; ii) tigecycline is bacteriostatic against Gram- tigecycline in subjects with secondary bacteremia: pooled results from 8 phase III
negative bacilli and a susceptibility breakpoint for Acinetobacter spp. clinical trials. Clin Infect Dis 2010;50:22938.
Geerlings SE, van Donselaar-van der Pant KA, Keur I. Successful treatment with
has not been adequately established; iii) some investigators have tigecycline of two patients with complicated urinary tract infections caused by
reported good success with tigecycline in these patients, while others extended-spectrum -lactamase-producing Escherichia coli. J Antimicrob Che-
have reported a high failure rate. Another area of concern is the use of mother 2010;65:20489.
Gordon NC, Wareham DW. A review of clinical and microbiological outcomes following
tigecycline against MDR pathogens in patients who develop sepsis: i) treatment of infections involving multidrug-resistant Acinetobacter baumannii with
standard tigecycline doses provide serum concentrations that are tigecycline. J Antimicrob Chemother 2009;63:77580.
below the MICs of most Gram-negative pathogens; ii) high success Herpers BL, Vlaminckx B, Burkhardt O, Blom H, Biemond-Moeniralam HS, Hornef M,
et al. Intravenous tigecycline as adjunctive or alternative therapy for severe
rates with tigecycline are not observed in bloodstream infections with
refractory Clostridium difcile infection. Clin Infect Dis 2009;48:17325.
these organisms without adequate source control; iii) a higher Iarikov D, Alexander J, Charles J, Tracy L, Nambiar S. Analysis of an increase in all-cause
mortality rate has been observed in patients receiving tigecycline mortality in tigecycline treated patients. Presented at: 51st Interscience Conference
on Antimicrobial Agents and Chemotherapy; September 1720, 2011; Chicago, IL;
for treatment of MDR pathogens than with comparator agents.
2011.
In conclusion, tigecycline continues to be an interesting antimi- Jones RN, Ferraro MJ, Reller LB, Schreckenberger PC, Swenson JM, Sader HS. Multicenter
crobial to study. Further investigations are needed in patients with studies of tigecycline disk diffusion susceptibility results for Acinetobacter spp. J Clin
bacterial diarrheas, UTIs, atypical mycobacterial infections, and Microbiol 2007;45:22730.
Karageorgopoulos DE, Kelesidis T, Kelesidis I, Falagas ME. Tigecycline for the treatment
osteomyelitis. Continued use of tigecycline for the treatment of of multidrug-resistant (including carbapenem-resistant) Acinetobacter infections:
MDR pathogens should be guided by data from previous studies. a review of the scientic evidence. J Antimicrob Chemother 2008;62:4555.
336 G.E. Stein, T. Babinchak / Diagnostic Microbiology and Infectious Disease 75 (2013) 331336
Keeney D, Ruzin A, Bradford PA. RamA, a transcriptional regulator, and AcrAB, an RND-
type efux pump, are associated with decreased susceptibility to tigecycline in
Enterobacter cloacae. Microb Drug Resist 2007;13:16.
Kelesidis T, Karageorgopoulos DE, Kelesidis I, Falagas ME. Tigecycline for the treatment
of multidrug-resistant Enterobacteriaceae: a systematic review of the evidence
from microbiological and clinical studies. J Antimicrob Chemother 2008;62:
895904.
Kim P, Wu Y-T, Cooper CA, Rochester G, Valappil T, Wang YY, et al. Meta-analysis of a
possible signal of increased mortality associated with cefepime use. Clin Infect Dis
2010;51:3819.
Krueger WA, Kempf VAJ, Peiffer M, Nagele U, Unertl KE, Schroeder TH. Treatment with
tigecycline of recurrent urosepsis caused by extended-spectrum--lactamase-
producing Escherichia coli. J Clin Microbiol 2008;46:81720.
Livermore DM. Tigecycline: what is it, and where should it be used? J Antimicrob
Chemother 2005;56:6114.
McGovern P, Wible M, El-Tahtawy A, Biswas P, Meyer D. Mortality imbalance in the
tigecycline phase 3 and 4 clinical trials. Presented at: 40th Annual Congress of
the Society of Critical Care Medicine; January 1519, 2011; San Diego, CA;
2011.
Meagher AK, Passarell JA, Cirincione BB, Van Wart SA, Liolios K, Babinchak T, et al.
Exposure-response analyses of tigecycline efcacy in patients with complicated
skin and skin-structure infections. Antimicrob Agents Chemother 2007;51:
193945.
Nathwani D. Tigecycline: clinical evidence and formulary positioning. Int J Antimicrob
Agents 2005;25:18592.
Nguyen T, Williams B, Trang E. Cefepime therapy and all-cause mortality. Clin Infect Dis
2009;48:9024.
Nix DE, Matthias KR. Should tigecycline be considered for urinary tract infections? A
pharmacokinetic re-evaluation. J Antimicrob Chemother 2010;65:13112.
Noskin GA. Tigecycline: a new glycylcycline for treatment of serious infections. Clin
Infect Dis 2005;41:S30314.
Olson MW, Ruzin A, Feyfant E, Rush III TS, O'Connell J, Bradford PA. Functional,
biophysical, and structural bases for antibacterial activity of tigecycline. Antimicrob
Agents Chemother 2006;50:215666.
Parker A, Naylor C. Subgroups, treatment effects, and baseline risks: some lessons from
major cardiovascular trials. Am Heart J 2000;139:95261.
Passarell JA, Meagher AK, Liolios K, Cirincione BB, Van Wart SA, Babinchak T, et al.
Exposure-response analyses of tigecycline efcacy in patients with complicated
intra-abdominal infections. Antimicrob Agents Chemother 2008;52:20410.
Prasad P, Sun J, Danner RL, Natanson C. Excess deaths associated with tigecycline after
approval based on noninferiority trials. Clin Infect Dis 2012;54:1699709.
Rubino CM, Bhavnani SM, Forrest A, Dukart G, Dartois N, Cooper A, et al.
Pharmacokinetics-pharmacodynamics of tigecycline in patients with community-
acquired pneumonia. Antimicrob Agents Chemother 2012;56:1306.
Rubino CM, Forrest A, Bhavnani SM, Dukart G, Cooper A, Korth-Bradley J, et al.
Tigecycline population pharmacokinetics in patients with community- or hospital-
acquired pneumonia. Antimicrob Agents Chemother 2010;54:51806.
Rubino CM, Ma L, Bhavnani SM, Korth-Bradley J, Speth J, Ellis-Grosse E, et al. Evaluation
of tigecycline penetration into colon wall tissue and epithelial lining uid using a
population pharmacokinetic model and Monte Carlo simulation. Antimicrob
Agents Chemother 2007;51:40859.
Ruzin A, Keeney D, Bradford PA. AdeABC multidrug efux pump is associated with
decreased susceptibility to tigecycline in Acinetobacter calcoaceticuscinetobacter
baumannii complex. J Antimicrob Chemother 2007;59:10014.
Ruzin A, Visalli MA, Keeney D, Bradford PA. Inuence of transcriptional activator RamA
on expression of multidrug efux pump AcrAB and tigecycline susceptibility in
Klebsiella pneumoniae. Antimicrob Agents Chemother 2005;49:101722.
Sabol MB, Cooper A, Castaing N, Dartois N, Maroko R, Dukart G. Phase 3 study
comparing tigecycline (TGC) and ertapenem (ERT) in patients (pts) with diabetic
foot infections (DFI) with and without osteomyelitis [abstract 133]. Presented at:
47th Annual Meeting of the Infectious Diseases Society of America; October 29
November 1, 2009; Philadelphia, PA; 2009.
Sader HS, Farrell DJ, Jones RN. Tigecycline activity tested against multidrug-resistant
Enterobacteriaceae and Acinetobacter spp. isolated in US medical centers (2005
2009). Diagn Microbiol Infect Dis 2011;69:2237.
Schafer JJ, Goff DA, Stevenson KB, Mangino JE. Early experience with tigecycline for
ventilator-associated pneumonia and bacteremia caused by multidrug-resistant
Acinetobacter baumannii. Pharmacotherapy 2007;27:9807.
Secondo G, Vassallo F, Solari N, Moresco L, Percivale P, Zappi L, et al. Empirical rst-line
treatment with tigecycline for febrile episodes following abdominal surgery in
cancer patients. Int J Antimicrob Agents 2010;36:4626.
Stein GE, Craig WA. Tigecycline: a critical analysis. Clin Infect Dis 2006;43:51824.
Swoboda S, Ober M, Hainer C, Lichtenstern C, Seiler C, Wendt C, et al. Tigecycline for the
treatment of patients with severe sepsis or septic shock: a drug use evaluation in a
surgical intensive care unit. J Antimicrob Chemother 2008;61:72933.
Tanaseanu C, Bergallo C, Teglia O, Jasovich A, Oliva ME, Dukart G, et al, 308 and 313
Study Groups. Integrated results of 2 phase 3 studies comparing tigecycline and
levooxacin in community-acquired pneumonia. Diagn Microbiol Infect Dis
2008;61:32938.
Tasina E, Haidich A-B, Kokkali S, Arvanitidou M. Efcacy and safety of tigecycline for the
treatment of infectious diseases: a meta-analysis. Lancet Infect Dis 2011;11:
83444.
T.E.S.T. Tigecycline Evalauation and Surveillance Trial. http://www.testsurveillance.com.
Accessed November 14, 2012.
Thamlikitkul V, Tiengrim S. Effect of different MuellerHinton agars on tigecycline disc
diffusion susceptibility for Acinetobacter spp. J Antimicrob Chemother 2008;62:
8478.
Van Wart SA, Owen JS, Ludwig EA, Meagher AK, Korth-Bradley JM, Cirincione BB.
Population pharmacokinetics of tigecycline in patients with complicated intra-
abdominal or skin and skin structure infections. Antimicrob Agents Chemother
2006;50:37017.
Vasilev K, Reshedko G, Orasan R, Sanchez M, Teras J, Babinchak T, et al. A phase 3, open-
label, non-comparative study of tigecycline in the treatment of patients with
selected serious infections due to resistant Gram-negative organisms including
Enterobacter species, Acinetobacter baumannii and Klebsiella pneumoniae. J
Antimicrob Chemother 2008;62(Suppl. 1):i2940.
Visalli MA, Murphy E, Projan SJ, Bradford PA. AcrAB multidrug efux pump is associated
with reduced levels of susceptibility to tigecycline (GAR-936) in Proteus mirabilis.
Antimicrob Agents Chemother 2003;47:6659.
Wilcox MH. Evidence for low risk of Clostridium difcile infection associated with
tigecycline. Clin Microbiol Infect 2007;13:94952.
Wyeth Pharmaceuticals Inc. Tygacil [tigecycline] for injection for intravenous use. Full
prescribing information. http://labeling.pzer.com/showlabeling.aspx?id=491.
Accessed July 13, 2012.
Yahav D, Lador A, Paul M, Leibovici L. Efcacy and safety of tigecycline: a systematic
review and meta-analysis. J Antimicrob Chemother 2011;66:196371.
Yusuf S, Wittes J, Probsteld J, Tyroler H. Analysis and interpretation of treatment
effects in subgroups of patients in randomized clinical trials. JAMA 1991;266:938.